Progressive Hippocampal Neuroarchitecture Changes in the 5×FAD Alzheimer's Disease Mouse Model.

BACKGROUND

Neuroplasticity and synaptic homeostasis are essential in regulating neuronal activity and behavioral functions within the hippocampus. Alzheimer's disease (AD) is characterized by progressive cognitive decline, pathological accumulation of amyloid β (Aβ) plaques and tau neurofibrillary tangles, neuroinflammation, and synaptic dysfunction. However, the temporal progression of neuroplasticity-related impairments in the hippocampus, a region particularly vulnerable to AD pathology, is not completely understood.

METHODS

This study examined age-dependent changes in behavioral performance and hippocampal structural plasticity in the 5×FAD (five familial Alzheimer's disease) mouse model at 3, 6, and 12 months of age.

RESULTS

The 5×FAD mice exhibited progressive impairments in fine motor coordination and hippocampal-dependent working memory compared to control. Corresponding increases were observed in the accumulation of Aβ and phosphorylated tau, glial activation, and inflammatory cytokine production in the hippocampus across all time points. Golgi staining revealed significant age-related reductions in dendritic complexity, including fiber crossing counts, total dendritic length, and branch points in the cornu ammonis 1 (CA1) and dentate gyrus (DG) hippocampal subregions. Dendritic spine density and morphology exhibited significant alterations in the CA1 apical/basal and DG subregions with advancing age. Furthermore, the expression of synaptic proteins, including activity-regulated cytoskeleton-associated protein (Arc) and postsynaptic density protein-95 (PSD-95), significantly declined at 6 and 12 months of age.

CONCLUSIONS

Our findings suggest a potential relationship between AD-related protein pathology, neuroinflammation, and structural plasticity impairments in the hippocampus. Collectively, these changes may contribute to disrupted synaptic transmission and behavioral deficits associated with AD pathology.